Alkine diols and processes of preparation



United States Patent 3,278,609 ALKINE DIOLS AND PROCESSES OF PREPARATION Herbert Kiippe and Karl Zeile, Ingelheim (Rhine), Germany, assignors to Boehringer Ingelheim Gesellschaft mit beschrankter Haftung, Ingelheim (Rhine), Germany, a corporation of Germany a v No Drawing. Filed Mar. 26, 1963, Ser. No. 267,916 Claims priority, appliclzitigg lgiegrmany, Aug. 19, 1960,

6 Claims. (51. 260-618) This is a continuation-in-part of copending application Serial No. 207,028, filed July 2, 1962, now abandoned, which in turn is a continuation-in-part of application Serial No. 131,467, file-d August 15, 1961, now abandoned.

This invention relates to novel alkine diols comprising one secondary and one tertiary carbinol group and to processes for their preparation.

More particularly, the present invention relates to novel alkine diols of a formula selected from the group consisting of R is a substituent of 1 to 8 carbon atoms selected from i the group consisting of methyl, carbocyclic aryl-alkyl and carbocyclic aryl.

Within the last few years the chemical group of unsaturated nitrogen-free diols has acquired considerable importance as tranquilizingand sleep-inducing agents, since a demand has developed for weaker pharmaceuticals free from habit-forming barbituric acid and barbiturates.

Among these unsaturated nitrogen-free diols are the While a number of alkine diols have been produced, they have the drawback of containing two ad- 1 alkine diols.

jacent tertiary carbinol groups which give rise to a rather unpleasant aromatic, burnt taste when taken orally.

It is an object of the present invention to obtain alkine diols having one secondary and one tertiary carbinol group, and an excellent sedative action.

It is a further object of the invention to obtain alkine diols of a formula selected from the group consisting of 3,278,609 Patented'Oct. 11, 1966 "ice.

wherein R through R have the meanings defined above.

Another object is to develop a process of obtaining said alkine diols.

These and other objects of the invention will become more apparent. as the description thereof proceeds.

We have made the discovery that certain alkine diols having only one tertiary carbinol group are devoid or almost devoid of an unpleasant taste and are excellent sedatives for oral administration.

These novel alkin'e'diols have a formula selected from the group consisting of wherein R R R R and R have the meanings defined above.

The compounds of the above formulas can be divided into two series, one where R is either hydrogen or lower alkyl and the second where R is a halogen. Among the alkine diols we prefer compounds having the structural formulas wherein R is a radical of l to 8 carbon atoms selected from the group consisting of alkyl, cycloalkyl, phenyl and halophenyl, R is methyl, R is a radical of 1 to 8 carbon atoms selected from the group consisting of alkyl and cycloalkyl, and R is a radical of 1 to 6 carbon atomsselected from the group consisting of methyl, phenyl and halophenyl.

Especially preferred are alkine diols of a formula se-- lected from the group consisting of OH H and

I R13 alrofi- -ozo nu wherein R is a radical selected from the group consisting of alkyl of 1 to 4 carbon atoms, phenyl and p-chloro phenyl, R is a member of the group consisting of hydrogen and bromine, R is methyl, R is a radical selected from the group consisting of alkyl of 1 to 4 carbon atoms and R is a radical selected from the group consisting of methyl, phenyl and p-chlorophenyl.

In accordance with the present invention, compounds of formulas I and Ia may be prepared by the following process in its several alternative procedures. Primarily this process involves the reaction of an a-hydroxy ketone of a formula selected from the group consisting of R1 R CH( J OH O (II) and Itswherein the radicals R R R and R have the above indicated meanings, with an alkine derivative of the general formula wherein R is selected from the group consisting of hydrogen and lower alkyl, and X is either a metal atom or the Grignard radical, -MgHal, wherein Hal represents a halogen atom.

In the event that R represents a hydrogen atom, it may, if desired, subsequently be replaced by a halogen atom in accordance with known methods.

The reaction proceeds in accordance with the following reaction formula, wherein the substituents R R R and X have the above indicated meanings:

In the following are given particularly advantageous embodiments of the process according to the invention.

If the reaction is carried out with metal compounds of the alkine, an alkali metal is preferably dissolved in liquid ammonia, accompanied by simultaneous addition of the alkine. The further reaction of the metal compounds of the alkines with the whydroxy ketones may be carried out at temperatures below 35 C. in liquid ammonia or, after evaporation of the ammonia and addition of an inert organic solvent, at temperatures between about 0 and 130 C. Examples of suitable solvents are benzene, toluene, xylene, dimethylformamide, etc. The metal compounds of the substances having the Formulas I and Ia, which are thus obtained, are subsequently transformed into the corresponding alkine diols of Formulas I and Ia by treatment with dilute acids or ammonium chloride.

If the Grignard compounds of Formula III.are reacted with the a-hydroxy ketones of the Formulas II and 11a above, the following embodiment of the process has proved to be advantageous. The Grignard compound of the alkine is prepared by known methods in an inert organic solvent, preferably tetrahydrofuran. Subsequently, the a-hydroxy ketone is added at temperatures between about 20 and +50, 0, the ratio of reactants being at least 2 mols of the Grignard compound per mol of whydroxy ketone. The reaction is preferably carried out in an atmosphere of nitrogen. After the reaction has gone to completion, the reaction mixture is decomposed with ammonium chloride or dilute acids, accompanied by cooling, and the desired product is isolated from the organic phase.

In the event that substituent R is a hydrogen atom, this acid hydrogen atom may, if desired, be replaced by halogen in the end product. For this purpose, the alkine compound is treated, in accordance with known methods, with a solution of an alkali metal hypohaliteat temperatures between and +30 C. The haloalk-ine diols formed thereby separate out of the aqueous phase in the form of a liquid or solid and may be isolated by customary methods.

Some of the a-hydroxy ketones used as starting compounds in the present process are also novel. They may, for example, be prepared in accordance with customary methods by means of a Grignard reaction with a-hydroxy carboxylic acid derivatives, as represented by the following reaction formula:

In this formula Y represents a carbonamide group or a nitrile group and the substituents R and R have the meanings previously defined.

For the preparation of compounds of Formula II above, wherein R is an alkyl or carhocyclic arylalkyl radical, it is also possible to subject metal compounds of alkines to an addition reaction with aldehyde and subsubsequently with water in accordance with known methods, as represented by the following reaction formula:

In this reaction formula R has the above indicated meaning, Me represents a metal atom and R is selected from the group consisting of a hydrogen atom, analkyl radical and a carbocyclic aryl radical, the radical CH -R forming the radical designated as R in Formula I.

The compounds prepared in accordance with the present invention are useful pharmaceuticals which are especially characterized by their sedative activities. At high dosages they also exhibit good hypnotic activities as well as narcotic activities. They are also characterized by their particularly low toxicity.

The following examples further illustrate the process according to the present invention and enable others skilled in the art to understood it more completely. It will be understood, however, that the invention is not limited to these particular embodiments.

Example 1.Preparati n of 3-p'henyl-penthe- (1)-3,4-di0l 11.5 gm. (0.5 mol) of sodium were introduced into 450 cc. of liquid ammonia. The sodium dissolved and the solution turned blue. At the same time a vigorous stream of acetylene is passed through the ammonia solution until the solution becomes colorless. Thereafter, a solution of 30 gm. (0.2 mol) of a-hydroxy pro-piophenone (Formula 'II, R =C H R =CH in 60 cc. of ether (absolute), accompanied by thorough cooling (internal temperature -40 C.) and vigorous stirring. The introduction of a gentle stream of acetylene was maintained. After removal of the cooling bath, the introduction of acetylene was continued and the solution was stirred until all of the ammonia had evaporated. The residue was covered with a layer of ether, and then ice was carefully introduced and the mixture was neutralized with hydrochloric acid (diluted in a ratio of 1:1). The ether phase was separated, the aqueous phase was shaken twice with ether, the ether extract solutions were combined and washed with dilute sulfuric acid and a sodium bircarbonate solution, dried over magnesium sulfate and distilled in vacuo.

3-phenyl-pentine-(1)-3,4-diol (Formula I, R =C H R =H, R =CH was obtained as a liquid residue.

B.P. at 0.06 mm./Hg: 8890 C.

Yield: 32 gm. (91% of theory).

Example 2.Preparati0n of 3-methyl-pentine- (1)-3,4-di0l Using the same procedure as described in Example 1, B-methyl-pentine-(l)-3,4-diol of the formula having a boiling point of 46 C. at 0.25 mm./I- Ig was v i p p from acetoin and acetylene. Example 9. Preparatugnztfiiglcyclohexyl pentme (1) x p reparation f -p Using the same procedure as described in Example 1,

Using the same procedure as described in Example 1, 5 gicYcloheXYLPentmen'gli'dlol'of the formula 3-ethyl-pentine-(1)-3,4-diol of the formula H H era-on- -ozon having a boiling point of 57-58" C. at 0.5 mm./Hg was H H prepared from 2-hydroxy-3-pentanone and acetylene. having a melting point of 11154130 was prepared Example of m flqftll l-cyclohexyl-Z-hydr-oxy-l-propanone and acetylene.

dial e product was obtained as a crystalline residue.

Using the same procedure as described in Example 1, Example I0'preparitgtl3oij;gichlomphenyLpemme- 3-n-propyl-pentine-(l)-3,4-diol of the formula Using the same procedure as described in Example 1,

11-03% 3-p-chlorophenyl-pentine-(1)-3,4-diol of the formula GEE-CH4- CECH 01 H OH having a boiling point of 56-5 8 C. at 0.06 mm./Hg was prepared from 2-hydroxy-3-hexanone and acetylene. Example 5.-Prepardtion of 3-is0pr0pyl-pentine-(1)-3,4-

dial on -on- --CECH on on Using the same procedure as described in Example 1, a 3 iSOproPy1 pentine (1) 3,4 .di01 f the f m l having a boiling point of 105-107 C. was prepared from 1-p-chlorophenyl-2-hydroxy-l-propanone and acetylene.

ISO-03H, Example 11.--Preparati0n of 3-phenyl- GH CH pentine-(1)-3,4-diol H H 11.5 gm. (0.5 mol) of sodium were introduced into having a melting point of 68-71 C. was prepared from 450 cc. of liquid ammonia. The sodium went into solu- 4-methyl-2-hydroxy-3-pentanone and acetylene. tionand the solution turned blue. At .the same time The product was obtained as a crystalline residue. acetylene was passed through the solution until it turned colorless. Thereafter, 200 cc. of toluene (anhydrous) Example 6-Prepamtwn of 40 Were added, and after removal of the cooling bath, the

dial mixture. was vigorously stirred until the ammonia had Usin the Same rocedure as described inEXamPle 1 quantitatively evaporated. The residual suspension was 3-n-but%/l-pentine-(l -3 4-diol of th formula admixed dropwlse with a solution of 30 gm. of a-hydroxy propiophenone (0.2 mol) in 100 cc. of toluene, while 11-04 1 v simultaneously continuing to pass a gentle stream of 435011 acetylene therethrough. Subsequently, the resulting mixture was stirred for eight hours on a water bath at a temperature of 60100 C. After the mixture had cooled, having a boiling point of 68-69 C. at 0.04 mm./Hg was small pieces of ice were added accompanied by cooling, prepared from 2-hydroxy-3-heptanone and acetylene. and the mixture was then neutralized with dilute hydrochloric acid (dilution ratio 1:1). After separation of the toluene phase, the aqueous phase was shaken with ether.

HOH

Example 7.-Prep'aration of 3-n-hexyl-pentine-(I )-3,4-

1101 Thereafter the organic phases were combined, dried over Using the same procedure as described in Example 1, 3:52? fi e ggg ai g zgg ggiy gi fiizg ff g '-1-3,4-d' thf ul 1 1 1 1 3 nhexylpentm e a H 3-phenyl-pentine-(1)-3,4-diol (Formula I,

-F R.= 6 5.R.=H. R.= H.) CHFGH C:OH I was obtained.

OH H, B.P. at 0.04 mrn./Hg: 84-87 C. having a boiling point of 86-87' c. at 0.02 mm./Hg was Example P -P y prepared from 2-hydroxy-3-nonanone and acetylene.

A solution of ethyl magnesium bromide in tetrax w rr p hydrofuran was prepared from 54.5 gm. (0.5 mol) of dlol ethyl bromide, 12 gm. of magnesium shavings and 250 cc. of tetrahydrofuran (anhydrous). Accompanied by Using the Same Procedure as described in Example stirring, acetylene was passed through the solution in an 3n'octylpentme'u)'34d11oftheformula 0 atmosphere of nitrogen; the solution foamed slightly bemCsH" cause of the liberation of ethane. While continuing to v pass acetylene through the solution, a solution of 23.2

CHPCEP 'CEGH gm. (0.2 mol) of 2-hydroXy-3-hexanone in 50 cc. of

OH OH tetrahydrofuran was added slowly at 0 C.,'.taking care I I that an excess of acetylene was always present. Nitrogen having a boiling point of 106 C. at 0.05 mm./Hg was was introduced simultaneously until the reaction had gone prepared from Z-hydroxy-B-undecanone and acetylene. to completion. The reaction mixture was then decom- Example 13.-Preparatin of 3-methyl-4- phenyl-butine- (1 -3,4-di0l Following the same order of steps as in Example 12, 1-phenyl-l-hydroxy-2-propanone was reacted with acetylene. After final removal of the solvent, 3-methyl-4- phenyl-butine-(1)-3,4-diol of the formula on, oH-d ozo1r was obtained as a solid crystalline residue which was purified by customary recrystallization steps. The product had a melting point of 62-65 C.

Example 14.Preparati0n of 3-methyl-4-pchlorophenyl-butine-(1)-3,4-di0l Following the same order of steps as in Example 12,

l-p-chlorophenyl-l-hydroxy-Z-pnopanone was reacted with acetylene. After final removal of the solvent, 3-methy1- 4-p c-hlorophenyl-butine-(1)-3,4-diol of the formula OH H was obtained as a solid crystalline residue which was purified by customary recrystallization steps. The prodnot has .a melting point of 74-76 C.

Example 15.Preparation of 1-br0m0-3-npropyl-pentine-(l -3,4-diol 180 gm. of potassium hydroxide were dissolved in 800 cc. of water, the resulting solution was cooled to 0 C., 25 cc. of bromine were slowly added, and the resulting mixture was shaken for thirty minutes with 38.9 gm. of 3-n-propyl-pentine-(1)-3,4diol. The organic phase was shaken several times with ether, the ethereal extract solution was washed twice with 25 cc. portions of 2 N sulfuric acid and twice with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the ether was distilled oif in vacuo. The residue, 1-bromo-3-n-propyl-pentine (l) 3,4 diol (Formula I, R =CH -CH CH R Br, R =CH weighing 59 gm., was fractionally distilled in vacuo.

R1. at 0.04 mm./Hg: 83-84" C. (36 gm.).

Example Iii-Preparation of 1-br0mo-3-phenyl-pentine- (1) -3,4-di0l 3-phenyl-pentine-(l)-3,4-diol was treated with an aqueous solution of potassium hypobromite according to the process of Example '15 and 1bromo-3-phenyl-pentine- (l)-3,4-diol of the formula OH,0H-oozOBr OH OH was obtained as a crystalline solid which was purified by recrystallization and had a melting point of 70-73 8 Example 17.Preparati0n of l-bromo-3-methyl-pentine- G (1 )-3,4-di0l 3-methyl-pentine-(1)-3,4-dio-1 was treated with an aqueous solution of potassium hypobromite according to the process of Example 15 and 1-bromo-3-methyl-pentine- (1)-3,4-diol of the formula CH3 OH3CH(I)CECB1 OH OH was obtained as a crystalline solid which was purified by recrystallization and had a melting point of 93-96 C.

Example 18.Preparation of 1-br0m0-3-ethyl-pentine- (1)-3,4-di0l Following the same procedure as in Example 15, 3- ethyl:pent1ne-(1)-3,4-di0l was reacted with an aqueous solution of potassium hypobromite and 1-bromo-3-ethylpentine-(l)-3,4-diol 0f the formula was recovered having a boiling point of 72-73.5 C. at 0.002 mm./Hg.

Example J9.Preparation of 1-br0m0-3-n-pr0pyl-pentine- (I -3,4-di0l Following the same procedure as in Example 15, 3- n-propyl-pent1ne-(1)-3,4-diol was reacted with an aqueous solution of potassium hypobromite and 1-bromo-3-n- .propyl-pentine-(l)-3,4-diol of the formula OH OH was recovered having a boiling point of 955 C. at 0.01 mm./Hg.

Example 20.Preparati0n of I-br0m0-3-is0pr0pylpentine-(1)-3,4-di0l was obtained as a crystalline solid which was purified by recrystallization and had a melting point of 83 C.

Example 21 .Preparazi0n of 1-br0m0-3-n-hexyl-pentine- (1)-3,4-di0l 3-n-hexyl-pentine-(l)-3,4-dio1 was treated with an aqueous solution of potassium hypozbromite according to the process of Example 15 and 1-brorno-3-n-hexyl-pentine- (1)-3,4-di0l of the formula n-C H1 OH -CH -OEOBr OH OH was obtained as a crystalline solid which was purified by recrystallization and had a melting point of 81-85 C Example 22.Preparation of 1-br0m0-3-cycl0hexylpentine-(1)-3,4-di0l Following the same procedure as in Example 15, 3- cyclo-hexyl-pentine-(1)-3,4-di0l was reacted with an aqueous solution of potassium hypobromite and l-bromo- 3-cyclohexyl-pentine-( l)-3,4-diol of the formula was recovered having a boiling .point of 114.5-115" C.

at 0.05 mm./ Hg.

Example 23 .-Preparati n of 1-br0m0-3-methyl-4-phenylbutine-(l -3,4-di0l Gr m-( L050 Br OH OH was obtained as a crystalline solid which was purified by recrystallization and had a melting point of 7778 C.

Among the various alloine diols of Formulas I and Ia we have found that certain of them, as indicated in the examples, are obtained as crystalline solids. These particular compounds, in addition to being devoid or practically devoid of the rather unpleasant aromatic, burnt taste of the prior art compounds having two tertiary carbinol groups, are obtained in crystalline form rather than as oily liquids. In view of the fact that all the prior art alkine diols and many of the alkine diols of the invention having one secondary and one tertiary carbinol group are found in an oily, liquid form, this crystalline state was totally unexpected.

The properties of these crystalline alkine diols makes it possible to substantially improve their purification by crystallization, to improve the tests for purity of the product, to improve packaging and storage and to improve weighing and dosing since they can be incorporated into powders and tablets.

Particularly useful in this connection are 3-methyl-4- phenyl butine ('1) 3,4 diol (I, R =CH R =H, R =C H 1 bromo 3 methyl-4-phenyl-butine-(l)- 3,4-diol (I, R =CH R ='B-r; R =C H 3-methyl-4- p-chlorophenyl-butine-(l)-3,4-diol (I, R =CH R =H, R =C1-C H and 1-bromo-3-isopropylpentine-(1)-3,4- diol (I, R =CH(CH R ='Br, R =CH For therapeutic applications the alkine diols of the in-v vention are administered in single doses of from 30 to 700 mg., preferably 100 to 500 mg, in admixture with customary inert fillers in the form of tablets, coated pills, syrups, capsules, etc. The compounds of the invention may also be administered in combination with other sedative or therapeutic agents.

The following are illustrative examples of various pharmaceutical compositions containing the alkine diols of the invention. The parts are parts by weight.

Tablets of 500 mg.

Composition: Parts 3-methyl-4-phenyl-butine-(l)-3,4-dio1 500 Corn starch 130 Finely dispersed silicic acid 7 Soluble starch 20 Magnesium stearate 3 Preparati0n.500 parts of the active ingredient are thoroughly admixed with 40 parts of the corn starch and with parts of a 25% starch solution and, if necessary, moistened with a small amount of water. The ingredients are thoroughly kneaded, forced through a screen of 1.5 mm.-mesh, and dried at 45 C. After drying, the granulate is again passed through a 1.5 mm.-mesh screen.

560 parts of the granulate are admixed with parts of corn starch,

7 parts of finely dispersed silicic acid, and

3 parts of magnesium stearate.

The mixture is pressed into table-ts having a diameter of 13 'mm. and a weight of 660 mg.

Tablets of 150 mg.

i Composition: Parts 3-methyl-4-phenyl-butine-(1)-3,4-diol 150 Lactose 340 Corn starch 200 Soluble starch 25 Finely dispersed silicic acid 7 Magnesium stearate 3 Preparation.-150 parts of the active ingredient are thoroughly admixed with 340 parts of lactose and patrlts of the corn starch, and the mixture is moistened wit parts of a 25% starch solution and, if necessary, with a small amount of water, thoroughly kneaded, passed through a 1.5 mm.-mesh screen, and dried at 45 C. Thereafter, the granulate is again passed through a 1.5 rum-mesh screen. 610 parts of the granulate are admixed with parts of corn starch, 7 parts. of finely dispersed silicic acid and 3 parts of magnesium stearate.

The mixture is pressed into flat tablets'with a diameter of 13 mm. and a weight of 725 mg.

Wafer capsule of 300 mg.

Preparatio n.The 3 methyl-4-phenyl-butine-(l)-3,4-

diol, the lactose and the corn starch are thoroughly ad-* mlxed with each other and the mixture is granulated with cc. of water by passing the moistened mass through a screen with a 0.7 mm.-mesh. The granulate is dried at 30 C. and 500 mg. portions of the dry granul-ate are filled into wafer capsules, size 1 (diameter 20 mm.).

Tablets mg.

Composition: Parts 1 bromo 3 methyl-4-phenyl-butine-(1)-3,4-

diol 150 Lactose 340 Corn starch 200 Soluble starch 25 Finely dispersed silicic acid 7 Magnesium stearate 3 Preparatin.150 parts of the active ingredients are thoroughly admixed with 340 parts of the lactose and 95 parts of the corn starch, and the mixture is moistened with 100 parts of a 25% starch solution and, if necessary, with a small amount of water, thoroughly kneaded, forced through a 1.5 mm.-mesh screen and dried at 45 C. Thereafter, the granulate is again passed through a 1.5 mm.-mesh screen.

610 parts of this granulate are admixed with 105 parts of corn starch,

7 parts of finely dispersed silicic acid and 3 parts of magnesium stearate.

The mixture is pressed into flat tablets with a diameter of 13 mm. and a weight of 725 mg.

Wafer capsules of 150 mg.

Composition for 1 capsule:

Mg. 1-bromo-3methyl-4-phenyl-butine-( 1)-3,4-diol 15 Lactose, powdered 250 Corn starch 100 'Preparati0n.The 1-bromo-3-methyl-4-phenyl-butine- (l)-3,4-diol, the lactose and the corn starch were thoroughly admixed with each other and the mixture was granulated with 100 cc. of water by passing the moist mixture through a 0.75 mm.-mesh screen. 500 mg. portions of this granulate, which had been dried at 30 C., are filled into wafer capsules, size 1 (diameter 20 mm.).

The alkine diols of the invention are useful sedatives as stated previously. The hypnotic and narcotic effects have been tested on various animals and the lethal dose (LD has also been determined.

The alkine diol was emulsified with 20% by weight of gum arabic and was tested in mice per 0s. The criterion for hypnotic effect was the occurrence of disturbances in ambulation and ataxia. A narcotic effect was assumed when the animals remained in the supine position. The median hypnotic, narcotic and lethal doses were calculated by the method of Litchfield and Wilcoxon.

A summary of the hypnotic (HD narcotic (ND and lethal doses (LD for some of the alkine diols of Formulas I and Ia is as follows:

during the beginning and subsiding phases of the hypnotic or narcotic effects. The animals did not tremble and during the narcotic stage they could not be awakened even by strong external stimulations.

The narcotic effect can also be demonstrated with small doses by the prolongation of the Evipan-sleep. When the animals are given 100 mg./ kg. of Evipan-sodium intraperitoneally and at the same time mg./kg. of B-methyl- 4-phenyl-butine-(1)-3,4-diol, the period of sleep increases by 25 to 30 minutes. After administration of mg./ kg. of 3-methyl-4-phenyl-butine-(1)-3,4-diol the increase in the period of sleep amounts to to minutes.

In analogous fashion, the hypnotic and narcotic effect in rats was determined. The results were:

HD 3 50 m g. kg. (graphically determined) ND =620 mg./ kg. (graphically determined) LD =1085 mg./ kg. (calculation according to Karber) Sedation is also achieved in dogs and cats by administration of 3-rnethyl-4-phenyl-butine-(1)-3,4-diol per os; in some of these animals a very deep sleep is also induced from which they are not easily awakened.

3-methyl-4-phenyl-butine-(1)-3,4-diol is useful as a tranquilizing and deep-sleep-inducing agent by peroral admin- I istration.

4-BROM0-3-METHYL4-PHENYLBUTINE- (1) -3,4-DIOL This substance is a solid, is tasteless on the tongue and is soluble in water to a minor extent. The sedative effects of this compound are very distinct; in test animals sleep is induced without passage through an excitation or trembling stage. Upon peroral testing on white mice, the following values were obtained for the hypnotic (HD narcotic (ND and lethal doses (LD HD50=55 mg./kg. ND50=320 mg./kg. LD50=650 rug/kg.

the group consisting of Among the alkine diols we have found most preferable 3-methyl-4-phenyl-butine-(l)-3,4-diol and its l-bromo analog.

3METHYL-4-PHENYL-BUTLNE- (1) -3,4-DIoL This substance is a solid crystalline product, which is practically odorless and is soluble in Water to an extent of 7 or 8% by Weight. As shown in the summary, this compound has the following hypnotic (HD narcotic (ND and lethal doses (LD when tested with mice per os.

HD5o 210 ND =410 mg./kg.

In contrast to the barbiturates, 3-methyl-4-phenyl-butine-(1)-3,4-diol does not exhibit any excitation symptoms R is a radical of 1 to 6 carbon atoms selected from the group consisting of methyl, phenyl and halophenyl.

awn-agate 3-methyl-4-phenyl-butine-( 1 )-3,4-di0l.

3-pheny1-pentine-( 1 )-3 ,4-diol.

. 3-n-propy1-pentine-(1 )-3 ,4-diol. 3-n-butyl-pentine-(1)-3 ,4-di01.

. 3-methy1-4-p-chloropheny1-butine-(1 )-3 ,4-dio1.

References Cited by the Examiner UNITED STATES PATENTS 1/ 1932 Straus et a1. 260-617 9/ 1957 Monroe 260-617 10/1960 Hofer et al 260-617 10/1960 Hofer et a1 260-617 11/1960 Feit 260-618 6/1961 Ashkenaz 167-52 7/1961 Tedeschi 260-617 8/1961 Robson 167-52 FOREIGN PATENTS 9/ 1961 France. 12/ 1962 Switzerland.

OTHER REFERENCES LEON ZITVER, Primary Examiner.

FRANK S. CACCIAPAGLIA, JR., Examiner.

P. L. SABATINE, J. E. EVANS, Assistant Examiners. 

1. AN ALKALINE DIOL OF A FORMULA SELECTED FROM THE GROUP CONSISTING OF 